tbuckley/cabot-search huggingface dataset:
Peptide emulsions in incomplete Freund’s adjuvant create effective nurseries promoting egress of systemic CD4<sup>+</sup>and CD8<sup>+</sup>T cells for immunotherapy of cancer
Authors: Marit M Melssen, Caroline T Fisher, Craig L Slingluff, Cornelis J M Melief
Journal: Journal for ImmunoTherapy of Cancer (2022)

Water-in-oil emulsion incomplete Freund’s adjuvant (IFA) has been used as an adjuvant in preventive and therapeutic vaccines since its development. New generation, highly purified modulations of the adjuvant, Montanide incomplete seppic adjuvant (ISA)-51 and Montanide ISA-720, were developed to reduce toxicity. Montanide adjuvants are generally considered to be safe, with adverse events largely consisting of antigen and adjuvant dose-dependent injection site reactions (ISRs). Peptide vaccines in Montanide ISA-51 or ISA-720 are capable of inducing both high antibody titers and durable effector T cell responses. However, an efficient T cell response depends on the affinity of the peptide to the presenting major histocompatibility complex class I molecule, CD4 + T cell help and/or the level of co-stimulation. In fact, in the therapeutic cancer vaccine setting, presence of a CD4 + T cell epitope seems crucial to elicit a robust and durable systemic T cell response. Additional inclusion of a Toll-like receptor ligand can further increase the magnitude and durability of the response. Use of extended peptides that need a processing step only accomplished effectively by dendritic cells (DCs) can help to avoid antigen presentation by nucleated cells other than DC. Based on recent clinical trial results, therapeutic peptide-based cancer vaccines using emulsions in adjuvant Montanide ISA-51 can elicit robust antitumor immune responses, provided that sufficient tumor-specific CD4 + T cell help is given in addition to CD8 + T cell epitopes. Co-treatment with PD-1 T cell checkpoint inhibitor, chemotherapy or other immunomodulatory drugs may address local and systemic immunosuppressive mechanisms, and further enhance efficacy of therapeutic cancer peptide vaccines in IFA and its modern variants. Blinded randomized placebo-controlled trials are critical to definitively prove clinical efficacy. Mineral oil-based adjuvants for preventive vaccines, to tackle spread and severity of infectious disease, induce immune responses, but require more studies to reduce toxicity.
Signaling snapshots of a serotonin receptor activated by the prototypical psychedelic LSD
Authors: Can Cao, Ximena Barros-Álvarez, Shicheng Zhang, Kuglae Kim, Marc A. Dämgen, Ouliana Panova, Carl-Mikael Suomivuori, Jonathan F. Fay, Xiaofang Zhong, Brian E. Krumm, Ryan H. Gumpper, Alpay B. Seven, Michael J. Robertson, Nevan J. Krogan, Ruth Hüttenhain, David E. Nichols, Ron O. Dror, Georgios Skiniotis, Bryan L. Roth
Journal: Neuron (2022)
Cell-type-specific integration of feedforward and feedback synaptic inputs in the posterior parietal cortex
Authors: Daniel J. Rindner, Archana Proddutur, Gyorgy Lur
Journal: Neuron (2022)

The integration of feedforward (sensory) and feedback (top-down) neuronal signals is a principal function of the neocortex. Yet, we have limited insight into how these information streams are combined by individual neurons. Using a two-color optogenetic strategy, we found that layer 5 pyramidal neurons in the posterior parietal cortex receive monosynaptic dual innervation, combining sensory inputs with top-down signals. Subclasses of layer 5 pyramidal neurons integrated these synapses with distinct temporal dynamics. Specifically, regular spiking cells exhibited supralinear enhancement of delayed-but not coincident-inputs, while intrinsic burst-firing neurons selectively boosted coincident synaptic events. These subthreshold integration characteristics translated to a nonlinear summation of action potential firing. Complementing electrophysiology with computational modeling, we found that distinct integration profiles arose from a cell-type-specific interaction of ionic mechanisms and feedforward inhibition. These data provide insight into the cellular properties that guide the nonlinear interaction of distinct long-range afferents in the neocortex.
Activation and expansion of presynaptic signaling foci drives presynaptic homeostatic plasticity
Authors: Brian O. Orr, Richard D. Fetter, Graeme W. Davis
Journal: Neuron (2022)

Presynaptic homeostatic plasticity (PHP) adaptively regulates synaptic transmission in health and disease. Despite identification of numerous genes that are essential for PHP, we lack a dynamic framework to explain how PHP is initiated, potentiated, and limited to achieve precise control of vesicle fusion. Here, utilizing both mice and Drosophila, we demonstrate that PHP progresses through the assembly and physical expansion of presynaptic signaling foci where activated integrins biochemically converge with trans-synaptic Semaphorin2b/PlexinB signaling. Each component of the identified signaling complexes, including alpha/beta-integrin, Semaphorin2b, PlexinB, talin, and focal adhesion kinase (FAK), and their biochemical interactions, are essential for PHP. Complex integrity requires the Sema2b ligand and complex expansion includes a ∼2.5-fold expansion of active-zone associated puncta composed of the actin-binding protein talin. Finally, complex pre-expansion is sufficient to accelerate the rate and extent of PHP. A working model is proposed incorporating signal convergence with dynamic molecular assemblies that instruct PHP.
GPR92 activation in islet macrophages controls β cell function in a diet-induced obesity model
Authors: Camila O. de Souza, Vivian A. Paschoal, Xuenan Sun, Lavanya Vishvanath, Qianbin Zhang, Mengle Shao, Toshiharu Onodera, Shiuhwei Chen, Nolwenn Joffin, Lorena M.A. Bueno, Rana K. Gupta, Da Young Oh
Journal: Journal of Clinical Investigation (2022)

The molecular mechanisms underlying obesity-induced increases in β cell mass and the resulting β cell dysfunction need to be elucidated further. Our study revealed that GPR92, expressed in islet macrophages, is modulated by dietary interventions in metabolic tissues. Therefore, we aimed to define the role of GPR92 in islet inflammation by using a high-fat diet–induced (HFD-induced) obese mouse model. GPR92-KO mice exhibited glucose intolerance and reduced insulin levels — despite the enlarged pancreatic islets — as well as increased islet macrophage content and inflammation level compared with WT mice. These results indicate that the lack of GPR92 in islet macrophages can cause β cell dysfunction, leading to disrupted glucose homeostasis. Alternatively, stimulation with the GPR92 agonist farnesyl pyrophosphate results in the inhibition of HFD-induced islet inflammation and increased insulin secretion in WT mice, but not in GPR92-KO mice. Thus, our study suggests that GPR92 can be a potential target to alleviate β cell dysfunction via the inhibition of islet inflammation associated with the progression of diabetes.
Lactate Dehydrogenase and its clinical significance in pancreatic and thoracic cancers
Authors: Annalisa Comandatore, Marika Franczak, Ryszard T. Smolenski, Luca Morelli, Godefridus J. Peters, Elisa Giovannetti
Journal: Seminars in Cancer Biology (2022)

The energy metabolism of tumor cells is considered one of the hallmarks of cancer because it is different from normal cells and mainly consists of aerobic glycolysis, fatty acid oxidation, and glutaminolysis. It is about one hundred years ago since Warburg observed that cancer cells prefer aerobic glycolysis even in normoxic conditions, favoring their high proliferation rate. A pivotal enzyme driving this phenomenon is lactate dehydrogenase (LDH), and this review describes prognostic and therapeutic opportunities associated with this enzyme, focussing on tumors with limited therapeutic strategies and life expectancy (i.e., pancreatic and thoracic cancers). Expression levels of LDH-A in pancreatic cancer tissues correlate with clinicopathological features: LDH-A is overexpressed during pancreatic carcinogenesis and showed significantly higher expression in more aggressive tumors. Similarly, LDH levels are a marker of negative prognosis in patients with both adenocarcinoma or squamous cell lung carcinoma, as well as in malignant pleural mesothelioma. Additionally, serum LDH levels may play a key role in the clinical management of these diseases because they are associated with tissue damage induced by tumor burden. Lastly, we discuss the promising results of strategies targeting LDH as a treatment strategy, reporting recent preclinical and translational studies supporting the use of LDH-inhibitors in combinations with current/novel chemotherapeutics that can synergistically target the oxygenated cells present in the tumor.
Precocious puberty in narcolepsy type 1: Orexin loss and/or neuroinflammation, which is to blame?
Authors: Silvia Melzi, Vincent Prevot, Christelle Peyron
Journal: Sleep Medicine Reviews (2022)

Narcolepsy type 1 (NT1) is a rare neurological sleep disorder triggered by postnatal loss of the orexin/hypocretin neuropeptides. Overweight/obesity and precocious puberty are highly prevalent comorbidities of NT1, with a close temporal correlation with disease onset, suggesting a common origin. However, the underlying mechanisms remain unknown and merit further investigation. The main question we address in this review is whether the occurrence of precocious puberty in NT1 is due to the lack of orexin/hypocretin or rather to a wider hypothalamic dysfunction in the context of neuroinflammation, which is likely to accompany the disease given its autoimmune origins. Our analysis suggests that the suspected generalized neuroinflammation of the hypothalamus in NT1 would tend to delay puberty rather than hastening it. In contrast, that the brutal loss of orexin/hypocretin would favor an early reactivation of gonadotropin-releasing hormone (GnRH) secretion during the prepubertal period in vulnerable children, leading to early puberty onset. Orexin/hypocretin replacement could thus be envisaged as a potential treatment for precocious puberty in NT1. Additionally, we put forward an alternative hypothesis regarding the concomitant occurrence of sleepiness, weight gain and early puberty in NT1.
Transcriptional and functional analyses of neoantigen-specific CD4 T cells during a profound response to anti-PD-L1 in metastatic Merkel cell carcinoma
Authors: Candice Church, Thomas Pulliam, Natalie Longino, Song Y Park, Kimberly S Smythe, Vladimir Makarov, Nadeem Riaz, Lichen Jing, Robert Amezquita, Jean S Campbell, Raphael Gottardo, Robert H Pierce, Jaehyuk Choi, Timothy A Chan, David M Koelle, Paul Nghiem
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Merkel cell carcinoma (MCC) often responds to PD-1 pathway blockade, regardless of tumor-viral status (~80% of cases driven by the Merkel cell polyomavirus (MCPyV)). Prior studies have characterized tumor-specific T cell responses to MCPyV, which have typically been CD8, but little is known about the T cell response to UV-induced neoantigens. Methods A patient in her mid-50s with virus-negative (VN) MCC developed large liver metastases after a brief initial response to chemotherapy. She received anti-PD-L1 (avelumab) and had a partial response within 4 weeks. Whole exome sequencing (WES) was performed to determine potential neoantigen peptides. Characterization of peripheral blood neoantigen T cell responses was evaluated via interferon-gamma (IFNγ) ELISpot, flow cytometry and single-cell RNA sequencing. Tumor-resident T cells were characterized by multiplexed immunohistochemistry. Results WES identified 1027 tumor-specific somatic mutations, similar to the published average of 1121 for VN-MCCs. Peptide prediction with a binding cut-off of ≤100 nM resulted in 77 peptides that were synthesized for T cell assays. Although peptides were predicted based on class I HLAs, we identified circulating CD4 T cells targeting 5 of 77 neoantigens. In contrast, no neoantigen-specific CD8 T cell responses were detected. Neoantigen-specific CD4 T cells were undetectable in blood before anti-PD-L1 therapy but became readily detectible shortly after starting therapy. T cells produced robust IFNγ when stimulated by neoantigen (mutant) peptides but not by the normal (wild-type) peptides. Single cell RNAseq showed neoantigen-reactive T cells expressed the Th1-associated transcription factor (T-bet) and associated cytokines. These CD4 T cells did not significantly exhibit cytotoxicity or non-Th1 markers. Within the pretreatment tumor, resident CD4 T cells were also Th1-skewed and expressed T-bet. Conclusions We identified and characterized tumor-specific Th1-skewed CD4 T cells targeting multiple neoantigens in a patient who experienced a profound and durable partial response to anti-PD-L1 therapy. To our knowledge, this is the first report of neoantigen-specific T cell responses in MCC. Although CD4 and CD8 T cells recognizing viral tumor antigens are often detectible in virus-positive MCC, only CD4 T cells recognizing neoantigens were detected in this patient. These findings suggest that CD4 T cells can play an important role in the response to anti-PD-(L)1 therapy.
Remibrutinib, a novel BTK inhibitor, demonstrates promising efficacy and safety in chronic spontaneous urticaria
Authors: Marcus Maurer, William Berger, Ana Giménez-Arnau, Koremasa Hayama, Vipul Jain, Adam Reich, Sibylle Haemmerle, Karine Lheritier, Pauline Walsh, Summer Xia, Julian Storim
Journal: Journal of Allergy and Clinical Immunology (2022)

Chronic spontaneous urticaria (CSU) is inadequately controlled in many patients and greatly affects quality of life. Remibrutinib, a highly selective, oral, novel covalent Bruton tyrosine kinase inhibitor, might be effective in CSU.This first-in-patient trial aimed to evaluate the efficacy and safety of remibrutinib in CSU treatment and characterize the dose-response.This randomized, double-blind, placebo-controlled, phase 2b dose-finding trial evaluated remibrutinib (12 weeks) in patients inadequately controlled with second-generation H1-antihistamines, with at least moderately active CSU, with or without prior anti-IgE treatment (NCT03926611). Patients received remibrutinib 10 mg once daily, 35 mg once daily, 100 mg once daily, 10 mg twice daily, 25 mg twice daily, 100 mg twice daily, or placebo (1:1:1:1:1:1:1 ratio). The main end points were weekly Urticaria Activity Score change from baseline at week 4 and safety.Overall, 311 patients were randomized. Reduced symptom score was observed for all remibrutinib doses from week 1 until week 12, with weekly Urticaria Activity Score change from baseline at week 4: -19.1 (10 mg once daily), -19.1 (35 mg once daily), -14.7 (100 mg once daily), -16.0 (10 mg twice daily), -20.0 (25 mg twice daily), -18.1 (100 mg twice daily), and -5.4 for placebo (nominal P < .0001 for all doses vs placebo). Most adverse events were mild or moderate, with no dose-dependent pattern.Remibrutinib was highly effective in the treatment of CSU over the entire dose range, with a rapid onset of action and a favorable safety profile.
The clinical landscape of cell-free DNA alterations in 1671 patients with advanced biliary tract cancer
Authors: J.E. Berchuck, F. Facchinetti, D.F. DiToro, I. Baiev, U. Majeed, S. Reyes, C. Chen, K. Zhang, R. Sharman, P.L.S. Uson Junior, J. Maurer, R.T. Shroff, C.C. Pritchard, M.-J. Wu, D.V.T. Catenacci, M. Javle, L. Friboulet, A. Hollebecque, N. Bardeesy, A.X. Zhu, J.K. Lennerz, B. Tan, M. Borad, A.R. Parikh, L.A. Kiedrowski, R.K. Kelley, K. Mody, D. Juric, L. Goyal
Journal: Annals of Oncology (2022)

Targeted therapies have transformed clinical management of advanced biliary tract cancer (BTC). Cell-free DNA (cfDNA) analysis is an attractive approach for cancer genomic profiling that overcomes many limitations of traditional tissue-based analysis. We examined cfDNA as a tool to inform clinical management of patients with advanced BTC and generate novel insights into BTC tumor biology.We analyzed next-generation sequencing data of 2068 cfDNA samples from 1671 patients with advanced BTC generated with Guardant360. We carried out clinical annotation on a multi-institutional subset (n = 225) to assess intra-patient cfDNA-tumor concordance and the association of cfDNA variant allele fraction (VAF) with clinical outcomes.Genetic alterations were detected in cfDNA in 84% of patients, with targetable alterations detected in 44% of patients. Fibroblast growth factor receptor 2 (FGFR2) fusions, isocitrate dehydrogenase 1 (IDH1) mutations, and BRAF V600E were clonal in the majority of cases, affirming these targetable alterations as early driver events in BTC. Concordance between cfDNA and tissue for mutation detection was high for IDH1 mutations (87%) and BRAF V600E (100%), and low for FGFR2 fusions (18%). cfDNA analysis uncovered novel putative mechanisms of resistance to targeted therapies, including mutation of the cysteine residue (FGFR2 C492F) to which covalent FGFR inhibitors bind. High pre-treatment cfDNA VAF was associated with poor prognosis and shorter response to chemotherapy and targeted therapy. Finally, we report the frequency of promising targets in advanced BTC currently under investigation in other advanced solid tumors, including KRAS G12C (1.0%), KRAS G12D (5.1%), PIK3CA mutations (6.8%), and ERBB2 amplifications (4.9%).These findings from the largest and most comprehensive study to date of cfDNA from patients with advanced BTC highlight the utility of cfDNA analysis in current management of this disease. Characterization of oncogenic drivers and mechanisms of therapeutic resistance in this study will inform drug development efforts to reduce mortality for patients with BTC.
APOBEC mutagenesis, kataegis, chromothripsis in EGFR-mutant osimertinib-resistant lung adenocarcinomas
Authors: P. Selenica, A. Marra, N.J. Choudhury, A. Gazzo, C.J. Falcon, J. Patel, X. Pei, Y. Zhu, C.K.Y. Ng, M. Curry, G. Heller, Y.-K. Zhang, M.F. Berger, M. Ladanyi, C.M. Rudin, S. Chandarlapaty, C.M. Lovly, J.S. Reis-Filho, H.A. Yu
Journal: Annals of Oncology (2022)
Die Chirurgie des Mediastinum und des Ductus thoracicus
Authors: Hans Killian
Journal: JAMA (1941)

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SPOP Mutations as a Predictive Biomarker for Androgen Receptor Axis–Targeted Therapy in <i>De Novo</i> Metastatic Castration-Sensitive Prostate Cancer
Authors: Umang Swami, Ryon P. Graf, Roberto H. Nussenzveig, Virginia Fisher, Hanna Tukachinsky, Alexa B. Schrock, Gerald Li, Jeffrey S. Ross, Nicolas Sayegh, Nishita Tripathi, Vinay Mathew Thomas, Geoffrey R. Oxnard, Emmanuel S. Antonarakis, Neeraj Agarwal
Journal: Clinical Cancer Research (2022)

Intensification of androgen deprivation therapy (ADT) with either docetaxel or androgen receptor axis-targeted therapies (ARAT) are the current standard of care for patients with metastatic castration-sensitive prostate cancer (mCSPC). However, biomarkers guiding treatment selection are lacking. We hypothesized that ADT intensification with ARAT, but not with docetaxel, would be associated with improved outcomes in patients with de novo (dn)-mCSPC harboring SPOP mutations.Patient-level data from a deidentified nationwide (U.S.-based) prostate cancer clinico-genomic database between January 2011 and December 2021 were extracted. Eligibility criteria: diagnosis of metastatic disease within 30 days of original prostate cancer diagnosis, genomic profiling of a tissue biopsy collected within 90 days of original diagnosis, and initiation of ARAT or docetaxel within 120 days of initial diagnosis. The log-rank test and Cox proportional hazards models were used to compare time to castration-resistant prostate cancer (TTCRPC) and overall survival (OS) for patients with and without SPOP mutations undergoing ADT intensification with ARAT or docetaxel.In the ARAT cohort, presence of SPOP mutation compared with wild-type was associated with more favorable TTCRPC [not reached (NR) vs. 16.7 months; adjusted HR (aHR), 0.20; 95% confidence interval (CI), 0.06-0.63; P = 0.006] and OS (NR vs. 27.2 months; aHR, 0.19; 95% CI, 0.05-0.79; P = 0.022). In contrast, SPOP mutation status was not associated with TTCRPC or OS in docetaxel-treated cohort.In real-world settings, SPOP mutations were associated with improved outcomes to ADT plus ARAT (but not ADT plus docetaxel) in patients with dn-mCSPC. This may serve as a predictive biomarker to guide treatment selection for patients with mCSPC.
Tumor microenvironmental signals reshape chromatin landscapes to limit the functional potential of exhausted T cells
Authors: B. Rhodes Ford, Paolo D. A. Vignali, Natalie L. Rittenhouse, Nicole E. Scharping, Ronal Peralta, Konstantinos Lontos, Andrew T. Frisch, Greg M. Delgoffe, Amanda C. Poholek
Journal: Science Immunology (2022)

Response rates to immunotherapy in solid tumors remain low due in part to the elevated prevalence of terminally exhausted T cells, a hypofunctional differentiation state induced through persistent antigen and stress signaling. However, the mechanisms promoting progression to terminal exhaustion in the tumor remain undefined. Using the low-input chromatin immunoprecipitation sequencing method CUT&RUN, we profiled the histone modification landscape of tumor-infiltrating CD8+ T cells throughout differentiation. We found that terminally exhausted T cells had unexpected chromatin features that limit their transcriptional potential. Terminally exhausted T cells had a substantial fraction of active chromatin, including active enhancers enriched for bZIP/AP-1 transcription factor motifs that lacked correlated gene expression, which was restored by immunotherapeutic costimulatory signaling. Reduced transcriptional potential was also driven by an increase in histone bivalency, which we linked directly to hypoxia exposure. Enforced expression of the hypoxia-insensitive histone demethylase Kdm6b was sufficient to overcome hypoxia, increase function, and promote antitumor immunity. Our study reveals the specific epigenetic changes mediated by histone modifications during T cell differentiation that support exhaustion in cancer, highlighting that their altered function is driven by improper costimulatory signals and environmental factors. These data suggest that even terminally exhausted T cells may remain competent for transcription in settings of increased costimulatory signaling and reduced hypoxia.